MOTIVATION: Medical image fusion has developed into an important technology, which can effectively merge the significant information of multiple source images into one image. Fused images with abundant and complementary information are desirable, which contributes to clinical diagnosis and surgical planning. RESULTS: In this article, the concept of the skewness of pixel intensity (SPI) and a novel adaptive co-occurrence filter (ACOF)-based image decomposition optimization model are proposed to improve the quality of fused images. Experimental results demonstrate that the proposed method outperforms 22 state-of-the-art medical image fusion methods in terms of five objective indices and subjective evaluation, and it has higher computational efficiency. AVAILABILITY AND IMPLEMENTATION: First, the concept of SPI is applied to the co-occurrence filter to design ACOF. The initial base layers of source images are obtained using ACOF, which relies on the contents of images rather than fixed scale. Then, the widely used iterative filter framework is replaced with an optimization model to ensure that the base layer and detail layer are sufficiently separated and the image decomposition has higher computational efficiency. The optimization function is constructed based on the characteristics of the ideal base layer. Finally, the fused images are generated by designed fusion rules and linear addition. The code and data can be downloaded at https://github.com/zhunui/acof. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.